Metabolic dysregulation is integral to the development and pathogenesis of many age-related diseases, including type 2 diabetes and obesity. Several mitochondrially encoded peptides have previously been shown to be secreted from cells and to act as regulatory signals for metabolic homeostasis, including MOTS-c, SHLP2, and humanin. Novel modified analogs of a newly identified mitochondrially encoded peptide, CB5064, have been synthesized and evaluated for plasma stability, activity in a broad screen of G protein-coupled receptor (GPCR) target engagement, and for potential biological activity in diet-induced obese (DIO) mice. In vitro evaluation demonstrated that CB5064 analogs interact with and activate the apelin receptor (APJ/AGTRL1/APLNR). The observed EC50 values of several novel CB5064 analogs at the apelin receptor were in the low µM range, in some cases achieving maximum responses similar to the natural substrate, Apelin-13. In DIO mice, once daily administration of the same series of CB5064 analogs demonstrated a range of effects on metabolic regulation, including significant reduction in body weight, selective fat mass loss, and improved glucose tolerance. The apelin receptor is widely expressed in tissues and appears to play a critical role in energy metabolism, cardiovascular function, fluid homeostasis, angiogenesis, and in diabetic complications. These mitochondria-based peptide analogs therefore represent an entirely new class of molecules with agonist activity at the apelin receptor and potential for use as a source of novel therapeutics for type 2 diabetes, cardiovascular disease, and other age-related disorders. Additional evaluation of the therapeutic potential of these peptides is ongoing. Disclosure K. Grindstaff: Employee; Self; CohBar, Inc. E. Stenger: None. R. Shang: Other Relationship; Self; CohBar Inc. T. Yu: None. W.C. Luo: None. V.V. Kim: None. D. Perez-Tilve: Research Support; Self; CohBar, Inc., Novo Nordisk A/S. K.C. Cundy: Employee; Self; CohBar, Inc. Stock/Shareholder; Self; CohBar, Inc.

Metabolic dysfunction and insulin resistance are common underlying factors in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and many age-related diseases, including obesity and type 2 diabetes. CB4211 is a novel peptide analog of MOTS-c, a mitochondrially encoded peptide with a potential role in metabolic homeostasis. CB4211 reduces free fatty acid release from cultured adipocytes, improves NAFLD activity score (NAS) in STAM® mice, and selectively decreases fat mass in DIO mice. We investigated the mechanism of action (MOA) of CB4211 in regulating fatty acid metabolism, glucose homeostasis, and insulin sensitivity. CB4211 potentiated insulin mediated inhibition of lipolysis in isoproterenol stimulated adipocyte cultures without changing maximal response, while CB4211 alone had no effect. Inhibitors of IR auto-phosphorylation (GSK183705A) or downstream PI3K/Akt signaling pathway components (wortmannin, Akti-1/2) abolished the antilipolytic effects of insulin alone and in combination with CB4211. Further supporting sensitization of insulin signaling, CB4211 enhanced insulin mediated phosphorylation of IR, IRS-1, and Akt, without affecting IGF mediated phosphorylation of IGF-1R. Consistent with activity through IR, CB4211 potentiated insulin induced reduction in glucose production in H4-IIE cells. The acute in vivo effect of CB4211 on insulin tolerance was determined in fasted DIO mice. Administration of CB4211 with insulin enhanced insulin sensitivity, prolonging the reduction in blood glucose levels compared to insulin alone. In conclusion, CB4211 potentiates insulin effects on fatty acid metabolism and glucose homeostasis by acting at the level of IR. The observed MOA of CB4211 therefore supports its potential utility for treatment of NASH, obesity, type 2 diabetes, and other metabolic disorders. Disclosure K. Grindstaff: Employee; Self; CohBar, Inc.. R. Magnan: None. R. Shang: Employee; Self; CohBar Inc. E. Stenger: Employee; Self; CohBar, Inc.. J.S. Holland: None. D. Perez-Tilve: Research Support; Self; Novo Nordisk A/S, Cohbar. K.C. Cundy: Employee; Self; CohBar, Inc.. Stock/Shareholder; Self; CohBar, Inc..

OBJECTIVE: To assess the pharmacokinetics of XP23829 formulations after repeated daily dosing. BACKGROUND: XP23829 is a novel prodrug of MMF that has shown efficacy in the mouse Experimental Autoimmune Encephalomyelitis (EAE) model of Multiple Sclerosis (MS). Based on a single dose Phase 1 study, two XP23829 formulations were selected for further evaluation. DESIGN/METHODS: This was a randomized, double-blind, placebo-controlled, multiple ascending, oral-dose study of Formulations 1 (delayed release) and 2 (extended release) of XP23829 in healthy adults in five sequential cohorts of 12 active and 3 placebo. Each cohort received 7 days at target dose after titration: Formulation 1 at 200 mg BID or 400 mg BID (fasted); Formulation 2 at 800 mg QD (fed or fasted) and 500 mg BID (fed). Each 200 mg of XP23829 contains 107 mg-eq MMF. A sixth cohort received Tecfidera® (dimethyl fumarate, BG-12) 240 mg BID (fasted; fed on Day 7). Pharmacokinetics of MMF in blood and plasma were determined on Day 7 (Days 6 and 7 for Tecfidera®). RESULTS: The average ratio of MMF in plasma vs whole blood was 1.6. Mean maximum MMF concentration (Cmax,ss) in plasma was 1490 and 2200 ng/mL for 200 and 400 mg BID Formulation 1, respectively; mean area under the curve over 24 hours (AUC24,ss) was 3670 and 6910 ng*hr/mL. Mean Cmax,ss in plasma for Formulation 2 was 1370, 1830, and 1170 ng/mL at 800 mg QD (fasted), 800 mg QD (fed) and 500 mg BID, respectively; AUC24,ss was 4490, 5080, and 5510 ng*hr/mL. XP23829 levels were below quantitation limits. Tecfidera® (fasted) mean Cmax,ss and AUC24,ss were 2170 ng/mL and 7010 ng*hr/mL. Intersubject AUC variability (%CV) was 14% for Formulation 1 compared to 27% for Tecfidera®. CONCLUSIONS: XP23829 formulations provide similar or more sustained MMF exposure compared to Tecfidera®. Results support evaluation of XP23829 for potential once- and twice-a-day dosing in MS. Study Supported by: XenoPort, Inc.

The objective of this study was to assess the efficacy, safety, and pharmacokinetics of XP21279-carbidopa in patients with Parkinson's disease who experience motor fluctuations compared with immediate-release carbidopa-levodopa tablets. XP21279 is a levodopa prodrug that is actively absorbed by high-capacity nutrient transporters expressed throughout the gastrointestinal tract and then rapidly converted to levodopa by carboxylesterases. XP21279-carbidopa sustained-release bilayer tablets were developed to overcome pharmacokinetic limitations of levodopa by providing more continuous exposure. Patients with motor fluctuations who required carbidopa-levodopa four or five times daily were optimized for 2 weeks each on carbidopa-levodopa four or five times daily and XP21279-carbidopa three times daily in a randomized sequence. Next, they received each optimized treatment for 2 weeks in a double-blind/double-dummy, randomized sequence. The primary outcome measure was change from baseline in daily off time at the end of each double-blind treatment period. All patients at 2 sites underwent pharmacokinetic analyses. Twenty-eight of 35 enrolled patients completed both double-blind treatments. The mean total daily off time was reduced from baseline by a mean (± standard error) of 2.7 hours (± 0.48 hours) for immediate-release carbidopa-levodopa and 3.0 hours (± 0.57 hours) for XP21279-carbidopa (P = 0.49). Among 11 patients who completed pharmacokinetic sampling on each optimized treatment, the percentage deviation from the mean levodopa concentration was lower (P < 0.05) for XP21279-carbidopa than carbidopa-levodopa. Both treatments had a similar incidence of new or worsening dyskinesias. XP21279-carbidopa administered three times daily produced a reduction in off time similar to that of carbidopa-levodopa administered four or five times daily, and the difference was not statistically significant. XP21279-carbidopa significantly reduced variability in levodopa concentrations compared with carbidopa-levodopa.

OBJECTIVE: To investigate pharmacokinetics, safety and tolerability of two formulations of XP23829 and dimethyl fumarate (DMF), including dynamic changes in lymphocyte and eosinophil counts. BACKGROUND: XP23829 is an innovative prodrug of monomethyl fumarate (MMF), the same active metabolite produced by DMF. Reductions in blood lymphocytes and increases in blood eosinophils are known effects of FAEs. DESIGN/METHODS: This randomized, double-blind, placebo-controlled, multiple ascending dose study of two formulations of XP23829 (delayed and extended release [ER]) was conducted in healthy adults enrolled into five sequential cohorts of 12 active and 3 placebo subjects. Each cohort received 7 days of target dose following a titration period. Daily doses ranged from 400 mg to 1000 mg (240 mg to 600 mg of DMF equivalents). An additional cohort received DMF (Tecfidera ® , BG-12) 240 mg BID. Clinical labs were assessed at screening, baseline, Day 8 (1 day after last target dose) and follow-up (8-10 days after last dose). RESULTS: Both XP23829 and DMF reduced blood lymphocytes, but the magnitude of the reductions trended more strongly with XP23829, even at similar MMF exposures when compared to DMF. At Day 8, the mean percent reduction in lymphocytes from baseline ranged from 36.9% to 46.7% across subjects dosed with XP23829 ER [compared to reductions of 14.8% for DMF and 8.3% for placebo]. Reductions were reversible, restoring to baseline levels at the follow-up visit. Eosinophils were increased by 85-161% (but stayed within normal limits) from baseline for XP23829, 22% for DMF and 20% for placebo. CONCLUSIONS: In healthy subjects, XP23829 dosed for 11 days resulted in greater reductions in blood lymphocytes and increases in eosinophils compared to DMF at similar MMF plasma concentrations. The implications related to the pharmacologic activity of XP23829 will be explored in future clinical studies. Study Supported by: XenoPort, Inc. Disclosure: Dr. Steinman has received personal compensation for activities with Biogen Idec, Teva Neuroscience, MedImmune, Sanofi-Aventis, and Bayer. Dr. Fox has received personal compensation for activities with Allozine, Avanir Pharmaceuticals, Biogen Idec, Novartis, Questcor, Teva Neuroscience, and Xenoport. Dr. Fox has received research support from Novartis. Dr. Lissin has received personal compensation for activities with XenoPort Inc. as an employee. Dr. Lissin holds stock and/or stock options in XenoPort Inc. Dr. Lissin has received research support from XenoPort Inc. Dr. Zomorodi has received personal compensation for activities with XenoPort, Inc. Dr. Zomorodi holds stock and/or stock options in Johnson and Johnson Pharmaceuticals. Dr. Zomorodi has received research support from XenoPort, Inc. Dr. Chen has received personal compensation for activities with XenoPort Inc. as an employee. Dr. Chen holds stock and/or stock options in XenoPort Inc. Dr. Chen has received research support from XenoPort Inc. Dr. Clark has received personal compensation for activities with XenoPort, Inc. as an employee. Dr. Clark has received research support from XenoPort, Inc. Dr. Cundy has received personal compensation for activities with Xenoport, Inc. as an employee. Dr. Cundy has received research support from Xenoport, Inc.

La presente invention concerne des fumarates de morpholinoalkyle, des compositions pharmaceutiques contenant les fumarates de morpholinoalkyle et des procedes d'utilisation des fumarates de morpholinoalkyle et des compositions pharmaceutiques pour traiter des troubles neurodegeneratifs, inflammatoires et auto-immuns, tels que la sclerose en plaques, le psoriasis, le syndrome du colon irritable, la rectocolite hemorragique, l'arthrite, la bronchopneumopathie obstructive chronique, l'asthme, la maladie de Parkinson, la maladie de Huntington et la sclerose laterale amyotrophique.

OBJECTIVE: To assess the pharmacokinetics (PK), safety and tolerability of four XP23829 formulations.BACKGROUND: Fumaric acid ester compounds have shown immuno-modulatory and neuroprotective effects in cell-based systems and preclinical models of Multiple Sclerosis (MS). Dimethyl fumarate (DMF), a fumaric acid ester prodrug of monomethyl fumarate (MMF), was effective in clinical trials of MS. XP23829 is a novel prodrug of MMF that had similar efficacy to DMF in a mouse model of MS but caused less stomach irritation than DMF in rats and monkeys.DESIGN/METHODS: This randomized, double-blind, crossover food effect study of the pharmacokinetics, safety and tolerability of XP23829 formulations enrolled 60 healthy adult subjects into five cohorts (12 subjects per cohort). Each cohort received single oral doses of one of four XP23829 formulations (107 mg eq of MMF) or placebo in both fed and fasted states.RESULTS: For all XP23829 formulations, MMF was observed in blood; intact prodrug and potential desmethyl metabolite were not detected. Formulation 1 produced mean (SD) maximum MMF concentrations (Cmax) of 529 (233) ng/mL fasted and 366 (320) ng/mL fed. MMF AUC was 762 (248) ng*h/mL fasted and 807 (445) ng*h/mL fed. In contrast, MMF release from Formulation 2 was more sustained and minimally affected by food: Cmax 143 (61) ng/mL fasted and 217 (89) ng/mL fed; AUC 625 (216) ng*h/mL fasted and 750 (242) ng*h/mL fed. Promoiety was cleared from blood with a half life around three hours. XP23829 was generally well-tolerated during the trial. All subjects completed both dosing periods. All AEs were mild. AEs reported in more than one subject and more frequently for XP23829 than for placebo were flushing and feeling hot, observed primarily for Formulation 1.CONCLUSIONS: The trial demonstrated that administration of formulations of XP23829 provides a range of MMF exposure profiles in blood, and supports further evaluation for potential once-a-day and twice-a-day treatments.Supported by: XenoPort, Inc.Disclosure: Dr. Lissin has received personal compensation for activities with XenoPort Inc. Dr. Lissin holds stock and/or stock options in XenoPort Inc. Dr.Luo is an employee of XenoPort. Dr. Luo has received research support for as an employee of XenoPort, Inc. Dr. Tai has received personal compensation for activities with XenoPort, Inc. as an employee. Dr. Zomorodi has received personal compensation for activities with XenoPort, Inc. as an employee. Dr. Zomorodi holds stock and/or stock options in Johnson and Johnson Pharmaceuticals. Dr. Zomorodi has received research support from XenoPort, Inc. Dr. Chen has received personal compensation for activities with XenoPort, Inc. Dr. Chen holds stock and/or stock options in XenoPort, Inc. Dr. Nguyen has received personal compensation for activities with XenoPort, Inc. as an employee. Dr. Nguyen has received research support from XenoPort, Inc. Dr. Yao has received personal compensation for activities with XenoPort, Inc. as an employee. Dr. Yao has received research support from XenoPort, Inc. Dr. Kim has received personal compensation for activities with XenoPort as an employee. Dr. Kim has received research support from XenoPort, Inc. Dr. Zou has received personal compensation for activities with XenoPort, Inc. as an employee. Dr. Zou has received research support from XenoPort, Inc. Dr. Phuong has received personal compensation for activities with XenoPort, Inc. Dr. Phuong has received research support from XenoPort, Inc. Dr. Cundy has received personal compensation for activities with Xenoport, Inc. Dr. Cundy has received research support from Xenoport, Inc.

L'invention concerne des procedes de traitement d'une maladie chez un patient, comprenant l'administration a un patient, qui a besoin d'un tel traitement, d'une quantite efficace sur le plan therapeutique d'un compose selectionne parmi : (i) le fumarate de monomethyle, (ii) un promedicament de fumarate de monomethyle et (iii) leurs combinaisons, la maladie etant choisie parmi la sclerose concentrique de Bâlo, la bronchiolite obliterante avec organisation pneumonique, la vasculite du systeme nerveux central, la maladie de Charcot- Marie-Tooth, l'ataxie infantile avec hypomyelinisation du systeme nerveux central, la retinopathie diabetique, la maladie du greffon contre l'hote, l'amyotrophie monomelique, la neurodegenerescence avec accumulation de fer dans le cerveau, la neurosarcoidose, les syndromes paraneoplasiques, la myelopathie necrotique subaigue, le syndrome de Susac et la myelite transverse.